BR112015022747B1 - kit for preventing stenosis and using a self-assembling peptide - Google Patents

Abstract

KIT FOR PREVENTION OF STENOSIS AND USE OF A SELF-ASSEMBLY PEPTIDE Materials and methods for the prevention of gastrointestinal obstruction are provided. A peptide comprising between about 7 amino acids and about 32 amino acids in a solution can be introduced at a target site. The peptide can undergo self-organization under physiological conditions and / or in the presence of a cation.

Description

SEQUENCE LISTING

[001] The patent application contains a sequence listing, which was submitted electronically in ASCII format and is incorporated herein by reference in its entirety. This ASCII copy, created on March 12, 2014, is named T2071-7008WC_SL.txt and is 29161 bytes in size.

FIELD OF DISSEMINATION

[002] This disclosure generally refers to the materials and methods that can be used in medicine, research and industrial applications. More particularly, this disclosure relates to materials and methods that can be used for the prevention of gastrointestinal obstruction, including membranes, hydrogels, compositions and solutions, which can be used in the treatment of gastric ESD-induced ulcers.

SUMMARY

[003] According to one or more aspects, a method for preventing gastrointestinal obstruction in an individual is provided. The method may include introducing a catheter into a gastrointestinal tract. The method may also comprise positioning an end of the catheter in a target area of the gastrointestinal tract where at least partial prevention of gastrointestinal obstruction is desired. The method may further comprise administering through the catheter a solution comprising a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids in an effective amount and in a concentration effective to form a hydrogel under gastrointestinal tract conditions to provide prevention gastrointestinal obstruction. The method may further comprise removing the catheter from the gastrointestinal tract.

[004] According to one or more aspects, a kit for the prevention of gastrointestinal obstruction in an individual is provided. The kit may comprise a solution comprising a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids in an effective amount and in a concentration effective to form a hydrogel under physiological conditions to allow the prevention of gastrointestinal obstruction. The kit can also provide instructions for administering the solution to a target area of the individual's gastrointestinal tract.

[005] According to one or more aspects, a method to facilitate the prevention of gastrointestinal obstruction in an individual may comprise providing a solution comprising a peptide comprising between about 7 amino acids and about 32 amino acids in an amount effective and in an effective concentration to form a hydrogel under physiological conditions to prevent gastrointestinal obstruction. The facilitating method may also comprise providing instructions for administering the solution to a target area of the gastrointestinal tract by introducing the solution through a catheter positioned in the gastrointestinal tract.

[006] According to one or more aspects, a macroscopic support consisting essentially of a plurality of self-assembling peptides is provided. Each of the self-assembling peptides comprises between about 7 amino acids and about 32 amino acids in an effective amount that is capable of being positioned within an injury area of the gastrointestinal tract to promote healing and to prevent gastrointestinal obstruction.

BRIEF DESCRIPTION OF THE DRAWINGS

[007] The attached drawings are not intended to be drawn to scale. For the sake of clarity, not all components can be marked.

[008] In the drawings: FIG. AI is an image of an ulcer before endoscopic submucosal dissection (ESD), according to some modalities; FIG. 1B is an image of an ulcer before ESD, according to some modalities; FIG. 1C is an image showing an area just after ESD, according to some modalities; FIG. 1D is an image showing the area 1 week after ESD and application of a peptide solution, according to some modalities; FIG. 1E is an image showing the area of 4 weeks after ESD and the application of peptide, according to some modalities; FIG. 1F is an image showing the area 8 weeks after ESD and peptide application, according to some modalities; FIG. 2A is an image showing esophageal cancer in an early stage, with circumferential dispersion, according to some modalities; FIG. 2B is an image showing an artificial ulcer with 4/5 circumferential dispersion after resection of the lesion using ESD, according to some modalities; FIG. 2C is an image showing a coating of a peptide solution, according to some modalities; FIG. 2D is an image showing an area treated 4 weeks after surgery, according to some modalities; and FIG. 2E is an image of the treated area 8 weeks after surgery, according to some modalities.

DETAILED DESCRIPTION

[009] Materials and methods of the present disclosure can prevent gastrointestinal obstruction.

[0010] Endoscopic mucosectomy (EMR) and endoscopic submucosal dissection (ESD) are major surgical options for resection of lesion sites, such as polyps and cancerous tumors in a digestive system or gastrointestinal tract. EMR and ESD are both minimally invasive surgeries. ESD can generally dissect wider areas of an injury site than EMR. ESD, therefore, can cause obstructions due to contraction / shrinkage of the scar during the healing process more often than EMR. However, both EMR and ESD procedures can cause injuries that induce post-surgical gastrointestinal obstruction during the course of healing. One form of gastrointestinal obstruction may be a stricture in the gastrointestinal tract during the course of healing. By stenosis, it is intended to mean a narrowing in the tubular organ or a structure, such as the gastrointestinal tract, which can lead to a partial or complete obstruction in the gastrointestinal tract.

[0011] Success of EMD and ESD may require a relatively high reduction in post-procedure bleeding rates. These rates can be approximately 1 percent for the esophagus, approximately 5 percent for the stomach, and approximately 2 percent for the colorectal. Current treatments for ESD-induced gastric ulcers may include being treated with a proton pump inhibitor for at least 8 weeks after the ESD procedure.

[0012] Individuals may normally need to undergo various balloon dilation and local steroid injection treatments, leading to a significant drop in quality of life. Currently, there are no options for preventive obstructions, or stenosis, due to the contraction of the scar during its healing process.

[0013] The present invention provides materials and methods for the prevention or reduction of an obstruction, such as a stenosis, in the gastrointestinal tract. The gastrointestinal tract can include any one or more of the following: mouth, throat, esophagus, stomach, small intestine, large intestine or colon, rectum, or colorectal, referred to as the distal portion of the colon and rectum.

[0014] The present invention also provides materials and methods for the prevention or reduction of an obstruction in the gastrointestinal tract. "Prevent" may include complete prevention of a gastrointestinal tract in which a wound, injury, or target area may return to a preoperative state, or in which the wound, injury, or the target area may return to a previous state the development of a polyp, tumor or other tissue that may require removal, which can be referred to as a "normal" state. Prevention can include at least partially preventing or at least partially reducing, which may include returning to a state that allows at least some relief from an obstruction of the gastrointestinal tract that returns a wound, injury, or the target area of a state less than The normal.

[0015] Materials and methods may comprise preventing or reducing a gastrointestinal obstruction in the gastrointestinal tract in an individual. As used herein, the term "individual" is intended to include human and non-human animals, for example, large animals, vertebrates, and primates. In certain embodiments, the individual is a mammalian individual, and in particular embodiments, the individual is a human individual. Although applications with humans are clearly envisaged, veterinary applications, for example, with non-human animals, are also envisaged here. The term "non-human animals" of the present invention includes all vertebrates, for example, non-mammals (such as birds, for example, chickens; amphibians, reptiles) and mammals, such as non-human, domesticated primates and agriculturally useful animals, for example. example, sheep, dogs, cat, cow, pig, rat, among others.

[0016] The prevention or reduction of obstruction can be partial or complete. Materials and methods can include administration, application, or injection of a self-assembling peptide, or a solution comprising a self-assembling peptide, or a composition comprising a self-assembling peptide, to a predetermined area or intended target area.

[0017] The term "self-assembling peptide" can refer to a peptide that can exhibit a structure in VW beta sheet, in aqueous solution in the presence of specific conditions to induce the structure of beta sheet. These specific conditions may include increasing the pH of a self-assembling peptide solution. The increase in pH can be an increase in pH to a physiological pH. Specific conditions may also include the addition of a cation, such as a monovalent cation, to a self-assembling peptide solution. Specific conditions may include conditions related to a gastrointestinal tract.

The self-assembling peptide can be an amphiphilic self-assembling peptide. By "amphiphilic" is meant that the peptide comprises hydrophobic moieties and hydrophilic moieties. In some embodiments, an amphiphilic peptide may comprise, consist essentially of, or consist of alternating hydrophobic and hydrophilic amino acids. When alternating, it is intended to include a series of three or more amino acids that alternate between a hydrophobic amino acid and a hydrophilic amino acid, and it does not need to include each and every amino acid in the peptide sequence alternating between a hydrophobic amino acid and a hydrophilic amino acid. The self-assembly peptide, also referred to herein as "peptide" can be administered to the predetermined or desired target area, in the form of a solution, composition, hydrogel, membrane, self-assembly peptide support or any other form. The hydrogel can also be referred to as a membrane or support throughout this description. The predetermined or desired target area may be at or near the site of an ESD or EMR, or another surgical resection or removal of tissue in the gastrointestinal tract. The predetermined or desired target area can be established based on the location of a polyp, tumor, such as a cancerous tumor, or another area that may have undergone a surgical procedure, or an accidental or intentional trauma.

[0019] The self-assembling peptide solution can be an aqueous self-assembling peptide solution. The self-assembling peptide can be administered, applied, or injected into a solution that is substantially cell-free, or cell-free. In certain embodiments, the self-assembling peptide can be administered, applied, or injected into a solution that is either cell-free or cell-free.

[0020] The self-assembling peptide can also be administered, applied, or injected into a solution that is substantially drug-free or drug-free. In certain embodiments, self-assembling peptide can be administered, applied, or injected into a solution that is drug-free or drug-free. In certain other embodiments, the self-assembling peptide can be administered, applied, or injected into a solution that is substantially cell-free and substantially drug-free. In still other embodiments, the self-assembling peptide can be administered, applied, or injected into a solution that is cell-free and drug-free.

[0021] The self-assembly peptide solution may comprise, consist of, or consist essentially of the self-assembly peptide. The self-assembling peptide can be in an unmodified or modified form. By modified, it is understood that the self-assembling peptide may have one or more domains that comprise one or more amino acids that, when supplied in solution, are not self-assembled. By unmodified, it is understood that the self-assembling peptide may not have any domains other than those that provide for self-assembly of the peptide. That is, an unmodified peptide consists of alternating hydrophobic and hydrophilic amino acids that can self-assemble into a beta sheet, and a macroscopic structure, such as a hydrogel.

[0022] The administration of a solution may comprise, consist of, or consist essentially of the administration of a solution comprising, consisting of, or consisting essentially of a self-assembly peptide comprising, consisting of, or consisting essentially of between about 7 amino acids and about 32 amino acids. Other peptides that you do not understand, consist of, or consist essentially of between about 7 amino acids and about 32 amino acids can be contemplated by this disclosure.

[0023] When alternating, it is intended to include a series of three or more amino acids that alternate between a hydrophobic amino acid and a hydrophilic amino acid, and it does not need to include each and every amino acid in the peptide sequence alternating between a hydrophobic amino acid and a hydrophilic amino acid.

[0024] Materials and methods may comprise delivering a self-assembling peptide to a predetermined or desired target. The peptide can be administered as a hydrogel or forms a hydrogel after administration. A hydrogel is a term that can refer to a colloidal gel, which is dispersed in water. The hydrogel can also be referred to as a membrane or support throughout this description. Systems and methods may also include applying a self-assembling peptide to a predetermined or desired target as a solution such as an aqueous peptide solution.

[0025] The term "administration" is intended to include, but is not limited to, applying, introducing or injecting the self-assembly peptide, in one or more of several ways, including, but not limited to, by itself, through solution, such as an aqueous solution, or by means of a composition, hydrogel, or a support, with or without additional components.

[0026] The method may comprise introducing an administration device into or near an individual's predetermined or desired target area. The method may comprise the introduction of a delivery device comprising at least one of the following: syringe, pipette, tube, catheter, syringe catheter, or other needle-based device for an individual's predetermined or desired target area. The self-assembly peptide can be administered via a syringe, pipette, tube, catheter, syringe catheter, or other needle-based device to an individual's predetermined or desired target area. The syringe needle measurement can be selected to provide an adequate flow of a composition, solution, hydrogel, or liquid from the syringe to the target area. This can be based on some modalities of at least an amount of self-assembling peptide in a composition, peptide solution, or a hydrogel to be administered, the concentration of the peptide solution, in the composition, or the hydrogel, and the viscosity of the solution peptide, composition, or hydrogel. The delivery device can be a conventional device or designed to perform at least one of the following: achieve a specific target area, achieve a specific dosage regimen, deliver a specific target volume, amount, or concentration, and accurately deliver to a target area.

[0027] The method of preventing or reducing a gastrointestinal obstruction may comprise introducing a catheter into the individual and positioning one end of the catheter in a predetermined area or target area, such as a portion of the gastrointestinal tract. The self-assembly peptide can be administered via a catheter to the target area, where at least a prevention or partial reduction in obstruction of the gastrointestinal tract is desired. The use of a catheter can provide more selective administration of the peptide to provide more accurate delivery to the target area. Selective administration of the peptide can allow improved and more incisive delivery of the peptide solution, composition, or hydrogel such that the prevention or reduction of a gastrointestinal obstruction or stenosis is successful and precisely positioned in the desired location. Selective administration can provide improved target delivery that markedly improves treatment positioning and effectiveness over the use of a syringe or other delivery device. Delivery devices that can be used in the systems, methods and kits of the disclosure may include a syringe, pipette, tube, catheter, syringe catheter, other needle-based device, tube or catheter.

[0028] The use of the catheter may include the use of attached devices, such as a guidewire used to guide the catheter in position, or an endoscope that can allow correct placement of the catheter and visualization of the target area, and / or the path to the target area. The endoscope can be a tube, which can comprise at least one of a light and a camera or other viewing device to allow images of the individual's body to be viewed. The guidewire or endoscope can be introduced into the individual through the gastrointestinal tract. For example, through the mouth, throat, esophagus, stomach, small intestine, large intestine or colon, or the rectum. The endoscope can be inserted into the gastrointestinal tract before introducing the catheter into the tract.

[0029] The use of the delivery device, such as a syringe, pipette, tube, catheter, syringe catheter, other needle-based device, catheter or endoscope may need to determine the diameter or size of the opening or tract in which it exists a target area, such that at least a portion of the syringe, pipette, tube, syringe catheter, other needle-like device, catheter or endoscope can enter the opening or tract to administer the peptide, peptide solution, composition, or hydrogel to the target area.

[0030] In certain embodiments, the hydrogel can be formed in vitroe administered to the desired location in vivo. In certain instances, this location may be the area where you want to prevent or reduce an obstruction. In other examples, this location can be upstream, downstream from the area, or substantially close to the area. It may be desirable to allow hydrogel migration to the area where it is desired to prevent or reduce an obstruction or to prevent or reduce stenosis. Alternatively, another process can position the hydrogel in the area where it is desired. The desired location or target area can be at least a portion of an area where the tissue has been removed, for example, in or around areas where a cancerous or precancerous tissue has been removed, where one or more tumors have been removed. removed, or a biopsy was performed. The desired location or target area can be an ulcer or injury induced by ESD or ERD.

[0031] In certain aspects of the present description, the hydrogel can be formed in vivo. A solution comprising the self-assembly peptide, such as an aqueous solution, can be inserted into an in vivo location or an individual's area to prevent or reduce an obstruction or prevent or reduce stenosis at the location. In certain examples, the hydrogel can be formed in vivo in one location, and allowed to migrate to the area, where it is desired to prevent or reduce an obstruction or to prevent or reduce stenosis. Alternatively, another process can place the hydrogel in the area, where it is desirable to prevent or reduce an obstruction or to prevent or reduce stenosis. The peptides of the present invention can be in the form of a powder, a solution, a gel, or the like. Since the self-assembling peptide gels in response to changes in the solution's pH and salt concentration, it can be distributed as a liquid that gels when in contact with an object during application or administration.

[0032] In some environments, the peptide solution may be a weak hydrogel and, as a result, may be administered via a delivery device, as described herein.

[0033] In accordance with one or more modalities, self-assembling peptides can prevent gastrointestinal obstruction. In at least some modalities, self-assembling peptides can facilitate the formation of mucosal epithelium to prevent or reduce the formation of postoperative scars. The prevention or reduction in the formation of postoperative scars provides, at least in part, for the prevention or reduction in gastrointestinal obstruction or stenosis. In certain embodiments, this may be because the hydrogel, once in place, provides support to allow infiltration of cells that promote healing of the target area.

[0034] The administration of the self-assembling peptides within the subcutaneous layer of the mucous membrane can induce an injury to float away from the fixed muscle layer and then be separated using high frequency. A hemostatic effect can also be obtained at the time of resection of the lesion, allowing a reduction in the degree of surgical difficulty and risk.

[0035] In accordance with one or more modalities, a macroscopic support is provided. The macroscopic support can comprise, consist essentially of, or consist of a plurality of self-assembling peptides, each of which comprises, consists essentially of, or consists of between about 7 amino acids and about 32 amino acids in an effective amount that is capable of to be positioned within an area of injury to a gastrointestinal tract to promote healing and to prevent a gastrointestinal obstruction.

[0036] According to some modalities, the self-assembling peptides can be amphiphilic, alternating between hydrophobic amino acids and hydrophilic amino acids. According to one or more modalities, an individual can be evaluated to determine the need to prevent gastrointestinal obstruction or stenosis. Once the assessment has been completed, a peptide solution to be administered to the individual can be prepared.

[0037] In some embodiments, a biologically active agent can be used with the materials and methods of the present disclosure. A biologically active agent can comprise a compound, including a peptide, DNA sequence, chemical compound, or organic or inorganic compound that can impart some activity, regulation, modulation or adjustment to a condition or other activity in an individual or an laboratory environment. The biologically active agent can interact with another component to provide this activity. The biologically active agent can be referred to as a medicament according to some embodiments of the present invention. In certain embodiments, one or more biologically active agents can be gradually released to the outside of the peptide system. For example, one or more biologically active agents can be gradually released from the hydrogel. Both in vitro tests in vivo have demonstrated this gradual release of a biologically active agent. The biologically active agent can be added to the peptide solution prior to administration to an individual, or it can be administered separately from the solution to the individual.

[0038] This disclosure refers to aqueous solutions, hydrogels, supports, and membranes, which comprise self-assembling peptides, sometimes referred to as self-assembling oligopeptides. The peptides can be comprised of a peptide having about 6 to about 200 amino acid residues. Self-assembling peptides can exhibit a beta-sheet structure, in aqueous solution in the presence of a physiological pH and / or a cation, such as a monovalent cation, or other conditions applicable to the gastrointestinal tract. The peptides can be amphiphilic and alternate between a hydrophobic amino acid and a hydrophilic amino acid. In certain embodiments, the peptide may comprise a first portion that can be amphiphilic, alternating between a hydrophobic amino acid and a hydrophilic amino acid, and another portion or region that is not amphiphilic.

[0039] Peptides can generally be stable in aqueous solutions and self-assemble into large, macroscopic structures, supports or matrices, when exposed to physiological conditions, neutral pH, or physiological salt levels. Once the hydrogel is formed, it may not decompose, or it may decompose or biodegrade after a period of time. The rate of decomposition can be based at least in part on at least one of the conditions and the sequence of amino acids in its surroundings.

[0040] By "macroscopic" it is understood to have dimensions big enough to be visible under magnification of 10 times or less. In preferred embodiments, a macroscopic structure is visible to the naked eye. A macroscopic structure can be transparent and can be two-dimensional or three-dimensional. Typically, each dimension is at least 10 pm in size. In certain embodiments, at least two dimensions are at least 100 pm, or at least 1000 pm in size. Often, at least two dimensions are at least 1-10 mm in size, 10-100 mm in size, or more.

[0041] In certain embodiments, the size of the filaments can be from about 10 nanometers (nm) to about 20 nm. The distance of the interlining can be from about 50 nm to about 80 nm.

[0042] "Physiological conditions" can occur in nature by a particular organism, cell system, or individual that may be in contrast to artificial laboratory conditions. The conditions can comprise one or more properties, such as one or more particular properties or one or more property ranges. For example, physiological conditions can include a temperature or temperature range, a pH or pH range, a pressure or pressure range, and one or more of the concentrations of the particular compounds, salts and other components. For example, in some instances, physiological conditions may include a temperature in the range of about 20 to about 40 degrees Celsius. In some examples, the atmospheric pressure can be about 1 atm. The pH can be in the neutral pH range. For example, the pH can be in the range of about 6 to about 8. Physiological conditions can include cations, such as monovalent metal cations that can induce the formation of the membrane or hydrogel. These can include sodium chloride (NaCl). Physiological conditions may also include a concentration of glucose, concentration of sucrose, or another concentration of sugar, between about 1 and about 20 mM. Physiological conditions may include local conditions of the mouth, throat, esophagus, stomach, small intestine, large intestine, and rectum.

[0043] In some embodiments, the self-assembling peptides can be peptides of between about 6 amino acids and about 200 amino acids. In certain embodiments, the self-assembling peptides can be peptides of at least about 7 amino acids. In certain embodiments, the self-assembly of peptides can be peptides of between about 7 amino acids and about 32 amino acids. In certain other embodiments, the self-assembling peptides can be peptides of between about 7 amino acids and about 17 amino acids. In certain other examples, the self-assembly of peptides can be peptides of at least 8 amino acids, at least about 12 amino acids, or at least about 16 amino acids.

[0044] Peptides can also be complementary and structurally compatible. Complementary refers to the ability of peptides to interact through ionized pairs and / or hydrogen bonds that form between their hydrophilic side chains, and structurally compatible refers to the ability of complementary peptides to maintain a constant distance between their skeletons peptides. Peptides having these properties participate in intermolecular interactions that result in the formation and stabilization of beta sheets at the level of the secondary structure and stranded filaments at the level of the tertiary structure.

[0045] Both homogeneous and heterogeneous mixtures of peptides characterized by the above mentioned properties can form macroscopic stable membranes, filaments and hydrogels. The peptides, which are self-complementary and self-compatible, can form membranes, filaments, and hydrogels from a homogeneous mixture. Heterogeneous peptides, including those that cannot form membranes, filaments, and hydrogels in homogeneous solutions, which are complementary and / or structurally compatible with each other, can also self-assemble into macroscopic membranes, filaments and hydrogels.

[0046] Membranes, filaments, and hydrogels can be non-cytotoxic. The hydrogels of the present invention can be digested and metabolized in an individual. Hydrogels can be biodegraded in 30 days or less. They are simple in composition, permeable, and are easy and relatively inexpensive to produce in large quantities. Membranes and filaments, hydrogels or supports can also be produced and stored in a sterile condition. Optimal lengths for membrane formation can vary according to at least one of the amino acid composition, solution conditions, and conditions at the destination site.

[0047] In certain embodiments, a method of preventing gastrointestinal obstruction in an individual is provided. The method may comprise introducing a catheter into a target area of the gastrointestinal tract where at least partial prevention of gastrointestinal obstruction is desired. The method may further comprise administering through the catheter a solution comprising a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids in an effective amount and in a concentration effective to form a hydrogel under conditions of the gastrointestinal tract to provide at least least a partial prevention of gastrointestinal obstruction. The method may further comprise removing the catheter from the gastrointestinal tract.

[0048] The method may also comprise the visualization of a target area or destination region that comprises at least a portion of the gastrointestinal tract. Viewing the target area or target region may comprise viewing the target region or target area during at least one identification of the target area of the gastrointestinal tract, introducing the catheter, positioning the catheter tip in the target area, administering the solution , removal of the catheter and monitoring of the gastrointestinal tract after removal of the catheter. Visualization of the target area or target region can provide selective administration of the solution to the gastrointestinal tract. Visualization can occur at any time before, during and after administration of the solution. Visualization can occur, for example, in a period of time at least about one week after administration, about four weeks after administration and about eight weeks after administration.

[0049] The solution to be administered can essentially consist of, or consist of, a self-assembling peptide comprising at least about 7 amino acids. The solution to be administered can essentially consist of, or consist of, a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids. The peptide can be amphiphilic and at least a portion of the peptide can alternate between a hydrophobic amino acid and a hydrophilic amino acid.

[0050] The facilitating methods of the present invention may comprise providing instructions for administration through a catheter of a solution comprising a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids in an effective amount and in a concentration effective to form a hydrogel under conditions of the gastrointestinal tract to prevent, at least partially, or reduce a gastrointestinal obstruction. The peptide can be amphiphilic and at least a portion of the peptide can alternate between a hydrophobic amino acid and a hydrophilic amino acid.

[0051] Methods of facilitating may comprise providing the solution comprising a self-assembling peptide comprising between about 7 amino acids and about 32 amino acids in an effective amount and in an effective concentration to form a hydrogel, under physiological conditions for at least partially prevent or reduce a gastrointestinal obstruction. The peptide can be amphiphilic and at least a portion of the peptide can alternate between a hydrophobic amino acid and a hydrophilic amino acid.

[0052] Methods of facilitating may include providing instructions for viewing a target area or target region that comprises at least a portion of the gastrointestinal tract. The method may comprise providing instructions to view the target area or target region, during at least one identification of the target area of the gastrointestinal tract, the introduction of a catheter, the placement of one end of the catheter in the target area, administration of the solution, removal of the catheter from the gastrointestinal tract, and monitoring of the gastrointestinal tract after removal of the catheter. Facilitation methods may include providing instructions for viewing the target region or target area by image using an endoscope. The method may comprise providing instructions for viewing the target area over a period of about a week, about four weeks, or about eight weeks after administration. Instructions can be given to monitor the area in or around the target area. Instructions for using the methods of the present invention can be given after a surgical procedure.

[0053] The amino acids of the self-assembling or amphiphilic peptides can be selected from d-amino acids, 1-amino acids, or combinations thereof. Hydrophobic amino acids can include Ala, Val, Ile, Met, Phe, Tyr, Trp, Ser, Thr and Gly. The hydrophilic amino acids can be basic amino acids, for example, Lys, Arg, His, Orn; acidic amino acids, for example, Glu, Asp; or amino acids that form hydrogen bonds, for example, Asn, Gin. Acidic and basic amino acids can be grouped into a peptide. The carboxyl and amino groups of the terminal residues can be protected or unprotected. Membranes or hydrogels can be formed in a homogeneous mixture of self-complementary and self-compatible peptides or in a heterogeneous mixture of peptides that are complementary and structurally compatible with each other. Peptides in accordance with the above criteria can self-assemble on macroscopic membranes under suitable conditions, described herein.

[0054] Self-assembling peptides can be composed of about 6 to about 200 amino acid residues. In certain embodiments, about 7 to about 32 residues can be used in self-assembling peptides, while in other embodiments, self-assembling peptides can have about 7 to about 17 residues. The peptides can be about 5 nm long.

[0055] The peptides of the present invention can include peptides having the repeat sequence of arginine, alanine, aspartic acid and alanine (Arg-Ala-Asp-Ala (RADA) (SEQ ID NO: 1)), and those peptide sequences can be represented by (RADA) P, where p = 2-50 (SEQ ID NO: 2).

[0056] Other peptide sequences can be represented by the self-assembling peptides both the repeat sequence of isoleucine, glutamic acid, isoleucine and lysine (Ile-Glu-Ile-Lys (IEIK) (SEQ ID NO: 3)), and such sequences peptides are represented by (IEIK) P, where p = 2-50 (SEQ ID NO: 4). Other peptide sequences can be represented by the self-assembly peptides having the repeat sequence of isoleucine, glutamic acid, isoleucine and lysine (Ile-Glu-Ile-Lys (IEIK) (SEQ ID NO: 3)), and such peptide sequences are represented by (lEIK) pI, where p = 2-50 (SEQ ID NO: 5).

[0057] Other peptide sequences can be represented by the self-assembling peptides with the repeat sequence of lysine, leucine, aspartic acid, and leucine (Lys-Leu-Asp-Leu (KLDL) (SEQ ID NO: 6)), and such peptide sequences are represented by (KLDL) P, where p = 2-50 (SEQ ID NO: 7). Other peptide sequences can be represented by the self-assembling peptides having the repeat sequence of lysine, leucine and aspartic acid (Lys-Leu-Asp (KLD) (SEQ ID NO: 8)), and these peptide sequences are represented by (KLD ) P, where p = 2-50 (SEQ ID NO: 9). As specific examples of self-assembling peptides according to the invention, it can be a self-assembling RADA16 peptide having the sequence Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala -Asp-Ala (RADA) 4 (SEQ ID NO: 10), an IEIK13 self-assembly peptide having the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys-Ile-Glu-Ile- Lys-Ile ( lEIK) al (SEQ ID NO: 11), an IEIK17 self-assembly peptide having the sequence Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys- Ile-Glu-Ile-Lys-Ile-Glu-Ile-Lys -Ile (IEIK) 4I (SEQ ID NO: 12) or a KLDL12 self-assembly peptide having the sequence Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu-Lys-Leu-Asp-Leu (KLDL) 3 ( SEQ ID NO: 13).

[0058] Each of the peptide sequences described herein can provide peptides comprising, consisting essentially of, and consisting of the recited amino acid sequences.

[0059] The present invention provides materials, methods, and kits for solutions, hydrogels, and supports comprising, consisting essentially of, or consisting of the peptides described herein.

[0060] An aqueous solution (water) of 1 percent by weight by volume (w / v) and 2.5 percent w / v of (RADA) 4 (SEQ ID NO: 10) is available as the peptide hydrogel PuraMatrix ™ product by 3-D matrix Co., Ltd.

[0061] Certain peptides may contain sequences that are similar to the RGD cell attachment ligand (Arginine-Glycine-Aspartic acid). The compatibility of these peptides to support cell growth in vitro was tested by introducing a variety of primary cells cultured and transformed into homopolymer sheets of Ala-Glu-Ala-Glu-Ala-Lys-Ala-Lys- Ala-Glu- Ala-Glu-Ala-Lys-Ala-Lys (AEAEAKAKAEAEAKAK (EAK 16) (SEQ ID NO: 14), RAD 16 (SEQ ID NO: 26), RADA16 (SEQ ID NO: 10), and RAD16 heteropolymers (SEQ ID NO: 26) and EAK16 (SEQ ID NO: 14) .RAD-based peptides may be of particular interest due to the similarity of this RGD sequence. The RAD sequence is a high affinity linker present in the matrix protein tenascin extracellular and is recognized by integrin receptors The peptide EAK 16 (SEQ ID NO: 14) and other peptides described herein were derived from a region of a yeast protein, zuotin.

[0062] The self-assembly of the peptides can be attributable to the hydrogen bond and the hydrophobic bond between the peptide molecules by the amino acids composing the peptides.

[0063] The self-assembling peptides of the present invention can have a nanofiber diameter in a range from about 10 nm to about 20 nm and an average pore size is in the range from about 5 nm to about 200 nm. In certain embodiments, the nanofiber diameter, pore size, and nanofiber density can be controlled by at least one of the concentration of the peptide solution used and the amount of peptide solution used, such as the volume of the peptide solution . As such, at least one of the specific concentration of the peptide in solution and a specific amount of the peptide solution to provide at least one of the following: desired nanofiber diameter, pore size, and density to adequately provide for an occlusion can be selected.

[0064] As used herein, an amount of a peptide, peptide solution or hydrogel effective to at least partially prevent or reduce a gastrointestinal obstruction, an "effective amount" or a "therapeutically effective amount" refers to an amount of the peptide, peptide solution or hydrogel, which is effective in single or multiple administration (injection or application) to an individual, in treating, or curing, alleviating, relieving or ameliorating an individual with a disorder more than expected in the absence of such treatment . This can include a particular concentration or range of peptide concentrations in the peptide or hydrogel solution and, in addition, or alternatively, a certain volume or range of volumes of the peptide or hydrogel solution. The method of facilitating may comprise providing instructions for preparing at least an effective amount and effective concentration.

[0065] The dosage, for example, volume or concentration, administered (for example, applied or injected) can vary depending on the shape of the peptide (for example, in a solution of peptide, hydrogel, or in a dry form, such as a form lyophilized) and the route of administration used. The exact formulation, route of administration, volume, and concentration can be chosen in view of the individual's condition and in view of the particular target area or location where the peptide solution, hydrogel, or other form of peptide will be administered . Lower or higher doses than those recited here can be used or required. Specific dosage and treatment regimens for any particular individual may depend on a variety of factors, which may include the specific peptide or peptides employed, the size of the area being treated, the desired thickness of the resulting hydrogel that can be positioned in the target area desired, and the duration of treatment time. Other factors that can affect specific dosage and treatment regimens include age, body weight, general health, sex, time of administration, rate of degradation, severity and course of the disease, condition or symptom, and the judgment of the attending physician . In certain embodiments, the peptide solution can be administered in a single dose. In other embodiments, the peptide solution can be administered in more than one dose, or multiple doses. The peptide solution can be administered in at least two doses.

[0066] An effective amount and effective concentration of the peptide solution can be selected to at least partially avoid or reduce gastrointestinal obstruction. In some embodiments, at least an effective amount and an effective concentration can be based, in part, on a size or diameter of the target area. In other embodiments, at least an effective amount and an effective concentration are based in part on the flow rate of one or more fluids in or near the target area. In still other embodiments, at least an effective amount and an effective concentration can be based in part on a dimension or diameter of a material being removed from the gastrointestinal tract, such as tissue, or a tumor.

[0067] In yet other embodiments, at least an effective amount and effective concentration can be based in part on at least one of the following: size or diameter of the target area, the flow rate of one or more fluids in or near the area target, and a dimension or diameter of a material being removed from the gastrointestinal tract, such as tissue, or a tumor.

[0068] The effective amount can be, as described here, an amount that can provide for prevention or at least partial reduction in a gastrointestinal obstruction. Various properties of the gastrointestinal tract can contribute to the selection or determination of the effective amount, including at least one of the following: size or diameter of the target area, the flow rate of one or more fluids in or near the target area, the pH at or near the target area, and the concentration of various salts at or near the target area. Additional properties that can determine the effective amount include several properties listed above, at various locations along a path where the peptide solution is delivered. For example, if the target area is located in the stomach, one or more properties of the stomach and / or one or more properties of the path to the stomach, for example, the esophagus may at least partially influence or effect the selection or determination of effective amount.

The effective amount can include volumes from about 0.1 milliliters (ml) to about 100 ml of a peptide solution. The effective amount can include volumes from about 0.1 ml to about 10 ml of a peptide solution. In certain embodiments, the effective amount can be about 0.5 ml. In other embodiments, the effective amount may be about 1.0 ml. In still other embodiments, the effective amount can be about 1.5 ml. In yet other embodiments, the effective amount can be about 2.0 ml. In some other embodiments, the effective amount can be about 3.0 ml. In certain embodiments, the effective amount can be about 0.1 ml to about 5 ml per 1 cm2 of the target area. In certain embodiments, the effective amount may be about 1 mL per 1 cm2 of target area. This effective amount can be used in relation to a concentration, such as 2.5 weight percent by volume of a peptide solution of the present disclosure.

[0070] In some embodiments, a more effective prevention or reduction of gastrointestinal obstruction can be achieved with a greater volume of administered peptide solution or a higher concentration of peptide in solution to be administered. This can allow a longer or thicker hydrogel to form in the target area, allowing for a more secure position of the hydrogel in the target area. It is possible that, if a sufficiently high volume is not selected, the hydrogel may not be effective in preventing or reducing a gastrointestinal obstruction in the target area for the desired period of time.

[0071] The concentration can be effective, as described here, in an amount that can provide a desired prevention or reduction in gastrointestinal obstruction. Various properties of the gastrointestinal tract can contribute to the selection or determination of the effective concentration, including at least one of a dimension or diameter of the target area, the flow rate of one or more fluids in or near the target area, and in one dimension or diameter of a material being removed from the gastrointestinal tract, such as tissue, or a tumor.

The effective concentration can include concentrations of peptide in the solution in a range of about 0.1 weight percent by volume (w / v) to about 10 percent w / v. The effective concentration can include the peptide concentrations in the solution in a range of about 0.1 percent w / v to about 3.5 percent w / v. In certain embodiments, the effective concentration can be about 1 percent w / v. In other embodiments, the effective concentration can be about 2.5 percent w / v. In yet other embodiments, the effective concentration can be about 3.0 percent w / v.

[0073] In certain embodiments, a peptide solution having a higher concentration of peptide can provide a more effective hydrogel that has the ability to stay in place and provide effective prevention or reduction of gastrointestinal obstruction. For the purpose of dispensing the peptide solution, higher concentrations of peptide solutions may become too viscous to allow for effective and selective administration of the solution. It is possible that, if a sufficiently high concentration is not selected, the hydrogel may not be effective in maintaining a prevention or reduction of gastrointestinal obstruction in the target area for the desired period of time.

[0074] The effective concentration can be selected to provide a solution that can be administered by injection or by other means using a particular diameter or measuring catheter or needle.

[0075] The methods of the disclosure contemplate single administration, as well as multiple administrations of a therapeutically effective amount of peptides, compositions, peptide solutions, membranes, filaments, and hydrogels as described herein. The peptides, as described herein, can be administered at regular intervals, depending on the nature, severity and extent of the individual's condition. In some embodiments, a peptide, composition, peptide solution, membrane, filament, or hydrogel can be administered in a single administration. In some embodiments, a peptide, composition, peptide solution, or hydrogel described herein is administered in various administrations. In some embodiments, a therapeutically effective amount of a peptide, composition, peptide solution, membrane, filament, or hydrogel can be administered periodically at regular intervals. The selected regular intervals can be based on any one or more of the initial peptide concentration of the solution administered, the amount administered, and the rate of degradation of the hydrogel formed. For example, after an initial administration, there may be a continuation after administration, for example, one week, two weeks, four weeks, six weeks, or eight weeks. The continuation administration may comprise administration of a solution having the same concentration of peptide and volume as the initial administration, or may comprise administration of a solution of lower or greater concentration of peptide and volume. The selection of the appropriate follow-up administration of the peptide solution can be based on images of the target area and the surrounding area of the target area and determination of needs based on the condition of the individual. The predetermined intervals can be the same for each continuation administration, or they can be different. In some embodiments, a peptide, a peptide solution, or a hydrogel can be administered chronically at predetermined intervals to maintain at least a partial reduction or partial prevention of gastrointestinal obstruction in an individual during the individual's life. The predetermined intervals can be the same for each continuation administration, or they can be different. This may be dependent on whether the hydrogel formed from the previous administration is partially or totally interrupted or reduced. Continuing administration may comprise administration of a solution having the same concentration of peptide and volume as the initial administration, or may comprise administration of a solution of lower or greater concentration of peptide and volume. The selection of the appropriate continuation administration of the peptide solution can be based on images of the target area and the surrounding area of the target area and determination of needs based on the condition of the individual.

The self-assembling peptides of the present invention, such as RADA16 (SEQ ID NO: 10), can be peptide sequences that lack a distinct physiologically or biologically active motif or sequence and, therefore, may not impair intrinsic cellular function . Physiologically active motifs can control numerous intracellular phenomena, such as transcription, and the presence of physiologically active motifs can lead to phosphorylation of proteins on the surface of intracytoplasmic cells or by enzymes that recognize the motifs. When a physiologically active motif is present in an occlusive agent in the peptide tissue, the transcription of proteins with different functions can be activated or suppressed. The self-assembling peptides of the present invention may not have such physiologically active motives and, therefore, do not carry this risk.

[0077] A sugar can be added to the self-assembling peptide solution to improve the osmotic pressure of the solution from hypotonicity to isotonicity, without reducing the effect of tissue occlusion, thereby allowing biological safety to be increased. In certain examples, the sugar can be sucrose or glucose.

[0078] The optimal lengths for the formation of the membrane can vary with the composition of amino acids. A stabilizing factor contemplated by the peptides of the present invention is that the complementary peptides maintain a constant distance between the peptide skeletons. Peptides that can maintain a constant distance by pairing are referred to here as structurally compatible. The interpeptide distance can be calculated for each pair of ionized or hydrogen bonds, having the sum of the number of unbranched atoms in the side chains of each amino acid in the pair. For example, lysine has 5 and glutamic acid has 4 unbranched atoms in its side chains, respectively. Other examples of peptides that can form membranes, hydrogels or supports in heterogeneous or homogeneous mixtures are listed in Table 1.

[0079] Amphiphilic sequence criteria, length, complementarity and structural compatibility applicable to heterogeneous peptide mixtures. For example, two different peptides can be used to form the membranes: peptide A, Val-Arg-Val-Arg-Val-Asp-Val-Asp-Val-Arg-Val-Arg-Val-Asp-Val-Asp (VRVRVDVDVRVRVDVD ) (SEQ ID NO: 66), has Arg and Asp as the hydrophilic residues and peptide B, Ala-Asp-Ala-Asp-Ala-Lys- Ala-Lys-Ala-Asp-Ala-Asp-Ala-Lys-Ala -Lys (ADADAKAKADADAKAK) (SEQ ID NO: 67), has Lys and Asp. Peptides A and B are complementary; Arg in A can form an ionized pair with Asp in B and Asp in A can form an ionized pair with Lys in B. Thus, in a heterogeneous mixture of peptides A and B, membranes probably form, but would be homogeneously composed of any of the A or B peptides.

[0080] Membranes and hydrogels can also be formed from heterogeneous mixtures of peptides, each of which alone does not form membranes, if they are complementary and structurally compatible with each other. For example, mixtures of (Lys-Ala-Lys-Ala) 4 (KAKA) 4 (SEQ ID NO: 15) and (Glu-Ala-Glu-Ala) 4 (EAEA) 4 (SEQ ID NO: 68) or (Lys-Ala- Lys-Ala) 4 (KAKA) 4 (SEQ ID NO: 15) and (Ala-Asp-Ala-Asp) 4 (ADAD) 4 (SEQ ID NO: 69) would be expected to form membranes, but not any of these peptides alone, due to the lack of complementarity.

[0081] The peptides, which are not perfectly complementary or structurally compatible, can be thought of as containing incompatible analogs to incompatible base pairs in the hybridization of nucleic acids. Incompatible containing peptides can form membranes if the breaking strength of the incompatible pair is dominated by the overall stability of the interpeptide interaction. Functionally, these peptides can also be considered as complementary or structurally compatible. For example, an incompatible pair of amino acids can be tolerated if it is surrounded by several perfectly compatible pairs on each side.

[0082] The peptides can be chemically synthesized or can be purified from natural and recombinant sources. Using chemically synthesized peptides can allow peptide solutions to be deficient in unidentified components, such as unidentified components derived from another animal's extracellular matrix. This property, therefore, can eliminate infection concerns, including the risk of viral infection compared to the original tissues derived from conventional biomaterials. This can eliminate infection problems, including infections, such as bovine spongiform encephalopathy (BSE), making the peptide highly safe for medical use.

[0083] The initial concentration of the peptide can be a factor in the size and thickness of the membrane, hydrogel, or support formed. In general, the higher the concentration of peptide, the greater the extent of the membrane or hydrogel formation. Hydrogels, or supports formed in higher concentrations of starting peptide (about 10 mg / mL) (about 1.0 percent w / v) may be thicker and therefore likely to be stronger.

[0084] Formation of membranes, hydrogels, or supports can be very fast, in the order of a few minutes. The formation of membranes or hydrogels can be irreversible. In certain modalities, training may be reversible, and in other modalities, training may be irreversible. The hydrogel can form instantly when administered to a target area. Hydrogel formation can occur within about one to two minutes of administration. In other examples, formation of the hydrogel can occur within about three to four minutes of administration. In certain embodiments, the time it takes to form the hydrogel may be based, at least in part, on one or more of the concentration of the peptide solution, the volume of applied peptide solution, and conditions in the area of application or injection ( for example, the concentration of monovalent metal cations in the application area, the pH of the area, and the presence of one or more fluids in or near the area). The process may be unaffected by a pH of less than or equal to 12, and by temperature. Membranes or hydrogels can form at temperatures in the range of about 1 to 99 degrees Celsius.

[0085] Hydrogels can remain in position in the target area for a period of time sufficient to provide a desired effect, using the methods and kits of the present disclosure. The desired effect may be at least partially preventing or reducing a gastrointestinal obstruction.

[0086] The desired effect, using the methods and kits of the present invention, can be for the treatment of areas or to aid in the healing of areas, in which a surgical procedure was performed in the gastrointestinal tract. For example, the desired effect, using the methods and kits of the present invention, can be for the treatment of areas or to aid in the healing of areas, in which the resection of the lesion sites, such as polyps and cancerous tumors in the gastrointestinal tract . Surgical procedures may include endoscopic mucosectomy (EMR) or endoscopic submucosal dissection (ESD).

[0087] The period of time in which the membranes or hydrogels can remain in the desired area can be one or more days, up to one or more weeks. In other examples, you can stay in the desired area for up to 30 days, or more. You can remain in the desired area indefinitely. In other examples, it can remain in the desired area for a long period of time, until it is naturally degraded or intentionally removed. If the hydrogel degrades naturally over a period of time, subsequent application or subsequent injection of the hydrogel to the same or different location can be performed.

[0088] In certain embodiments, the self-assembling peptide may be prepared with one or more components that may allow greater effectiveness of the self-assembling peptide or may provide another action, treatment, therapy, or otherwise interact with one or more components of the individual. For example, additional peptides comprising one or more biologically active or physiologically active amino acid sequences or motifs can be included as one of the components, along with the self-assembling peptide. Other components can include biologically active compounds, such as a drug or other treatment that can provide some benefit to the individual. For example, a cancer treatment drug or anticancer drug can be administered with the self-assembly peptide, or it can be administered separately.

[0089] The peptide, peptide solution, or hydrogel may comprise small molecular drugs to treat the individual or to prevent hemolysis, inflammation and infection. Small molecular drugs can be selected from the group consisting of glucose, sucrose, purified sucrose, lactose, maltose, trehalose, dextran, iodine, lysozyme chloride, dimethylisopropylazulene, tocopheryl tretinoin, povidone-iodine, alpha-alprostadyl alcohol, aniseed alcohol , isoamyl salicylate, α-a, dimethylphenylethyl alcohol, bacdanol, helional, silver sulfadiazine, sodium bucladesin, alprostadil alfadex, gentamicin sulfate, tetracycline hydrochloride, sodium fusidate, calcium mupirocin hydrate and isoamyl benzoate. Other small molecular drugs can be contemplated. Protein-based drugs can be included as a component to be administered, and can include erythropoietin, tissue-type plasminogen activator, synthetic hemoglobin and insulin.

[0090] A component can be included to protect the peptide solution against rapid or immediate formation in a hydrogel. This can include an encapsulated delivery system that can degrade over time to allow a controlled time release of the peptide solution to the target area to form the hydrogel over a predetermined and desired period of time. Biodegradable, biocompatible polymers can be used, such as ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.

[0091] Any of the components described herein can be included in the peptide solution or can be administered separately from the peptide solution. In addition, any of the methods and methods of facilitating provided herein can be performed by one or more parties.

[0092] A peptide, peptide solution, or hydrogel of the disclosure can be provided in a kit. Instructions for administering the solution to a target area of an individual's gastrointestinal tract can also be provided in the kit. The peptide solution may comprise a self-assembling peptide comprising between about 7 amino acids and about 32, in an effective amount and concentration effective to form a hydrogel to at least partially prevent or reduce gastrointestinal obstruction. The instructions for administering the solution may comprise methods for administering the peptide, peptide solution, or hydrogel provided herein, for example, by an administration route described herein, in a dose, volume or concentration, or planning of administration . The peptide can be amphiphilic and at least a portion of the peptide can alternate between a hydrophobic amino acid and a hydrophilic amino acid.

[0093] The kit can also include informational materials. The information material can be descriptive, instructional, or marketing other material that relates to the methods described here. In one embodiment, the information material may include information on the production of the peptide, peptide solution, or hydrogel described herein, the physical properties of the peptide, composition, peptide or hydrogel solution, concentration, volume, size, dimensions, date of expiration, and batch or production location.

[0094] The kit can also optionally include a device or materials to allow administration of the peptide or peptide solution to the desired area. For example, a syringe, pipette, tube, catheter, syringe catheter, or other needle-based device can be included in the kit. In addition, or alternatively, the kit may include a guidewire, endoscope, or other monitoring equipment to provide selective administration of the peptide solution to the target area.

[0095] The kit may comprise, in addition to or alternatively, other components or ingredients, such as components that can assist in positioning the peptide solution, hydrogel or support. Instructions can be provided in the kit to combine a sufficient amount or sufficient volume of the peptide solution with a sucrose solution, which may or may not be provided with the kit. Instructions can be provided for diluting the peptide solution to administer an effective concentration of the solution to the target area of the gastrointestinal tract. The instruction can describe dilution of the peptide solution with a diluent or solvent. The diluent or solvent can be water. Instructions can also be provided for determining at least an effective solution concentration and an effective amount of the solution for the target area. This can be based on several parameters discussed here, and can include the diameter of the lesion or wound in the target area.

[0096] Other components or ingredients may be included in the kit, in the same or in different compositions or containers than the peptide, peptide solutions, or hydrogel. The one or more components that may include components that may allow for greater effectiveness of the self-assembling peptide or may provide another action, treatment, therapy, or otherwise interact with one or more components of the individual. For example, additional peptides comprising one or more biologically active or physiologically active sequences or motifs can be included as one of the components, together with the self-assembling peptide. Other components can include biologically active compounds, such as a drug or other treatment that can provide some benefit to the individual. For example, a cancer treatment drug or anticancer drug can be administered with the self-assembly peptide, or it can be administered separately. The peptide, peptide solution, or hydrogel may comprise small molecular drugs to treat the individual or to prevent hemolysis, inflammation, and infection, as disclosed herein. A sugar solution, such as sucrose solution, can be supplied with the kit. The sucrose solution can be a 20% sucrose solution.

[0097] Other components that are described here can also be included in the kit.

[0098] In some embodiments, a component of the kit is stored in a sealed bottle, for example, with a rubber or silicone closure (for example, polybutadiene or polyisoprene closure). In some embodiments, a component of the kit is stored under inert conditions (for example, under nitrogen or another inert gas such as argon). In some embodiments, a component of the kit is stored under anhydrous conditions (for example, with a desiccant). In some embodiments, a component of the kit is stored in a light-blocking container, such as an amber bottle.

[0099] As part of the kit or separated from the kit, syringes or pipettes can be preloaded with a peptide, peptide solution, or hydrogel, as disclosed herein. Methods to instruct a user to deliver a self-assembling peptide solution to a syringe or pipette, with or without the use of other devices, and to administer this to the target area through the syringe or pipette, with or without the use of other devices, is provided. Other devices may include, for example, a catheter with or without a guidewire.

[00100] In some embodiments of the present description, self-assembling peptides can be used as a coating on a device or an instrument such as a stent or catheter, to suppress fluid leakage from the body. Self-assembling peptides can also be incorporated or attached to a support, such as gauze or bandage, or a coating, which can provide a therapeutic effect to an individual, or which can be applied within a target area. Self-assembling peptides can also be soaked in a sponge for use.

[00101] Membranes can also be useful for culturing cell monolayers. Cells prefer to adhere to non-uniform charged surfaces. The charged residues and conformation of protein membranes promote cell adhesion and migration. The addition of growth factors, such as fibroblast growth factor, to the peptide membrane can further improve fixation, cell growth and neurite growth.

[00102] The function and advantage of these and other modalities of the methods and kits described here will be more fully understood from the example below. The following example is intended to illustrate the benefits of the treatment approach described, but does not exemplify the full scope of the treatment.

EXAMPLES Example 1

[00103] The test was performed on humans in order to determine the ability of the described peptides to prevent gastrointestinal obstruction. The individuals submitted to colorectal, esophageal and gastric endoscopic dissection of the submucosa (ESD) by nine endoscopists participated in the test. Individuals who received antithrombotic therapy were included in the study, but such medications were no longer administered before the procedures. Cases with perforation and coagulopathy (International Standardized Ratio (INR)> 3), despite the management of anticoaculation after heparin bridge therapy (HBT) were excluded. Figures 1A and 1B show an ulcer before ESD.

[00104] After the ESD procedure, a self-assembly peptide was administered to a target area in the subject. Figure 1C shows an area just after ESD. For each 1 cm2 of tumor, 1 mL of RADA16 peptide self-assembly, in the form of PuraMatrix ™ peptide hydrogel by 3-D Matrix, LTD. (2.5 percent w / v) was applied to the ESD-induced ulcer using a catheter immediately after the procedure. A single dose proton pump inhibitor was administered in cases of gastric ESD for 8 weeks starting on the morning of the procedure. Gastric ulcer stages were evaluated by endoscopy as active, healing or healing at 1, 4, and 8 weeks after ESDs, and the application of the self-assembly peptide. The primary goal was the post-ESD bleeding rate. Secondary goals include the rate of transition to the healing and healing stages of gastric ESD-induced ulcers.

[00105] Of the 117 individuals recruited, 114 patients with 124 injuries (esophagus 18; stomach 42; colorectal 64) were enrolled for analysis of results and 3 individuals were excluded due to perforations and 1 with coagulopathy.

[00106] Of the 114 patients, 22 (19%) were previously on antithrombotic therapy including 6 (5%) requiring HBTs. The mean size of the resection specimen was 40 ± 16 mm (esophagus 41 ± 20 mm; stomach 36 ± 12 mm; colorectal 43 ± 16 mm). The post-ESD bleeding rate was 1.6% (2/124) (esophagus 0%; stomach 2.4% (1/43 '95% confidence interval, 0.04% to 12.3%) ; coloretal 1.6% (1/64 '95% Cl, 0.02% to 1.6%). All post-ESD bleeding was successfully controlled by endoscopy without the need for blood transfusion. for the 1-week healing stage, it was 98%, Figure 1D shows the area of 1 week after ESD and peptide application, and continuation endoscopy showed a scar stage in 21% and 97% in 4 and 8 weeks, respectively. Figure 1E shows the area of 4 weeks after the application of ESD and peptides Figure 1F shows the area of 8 weeks after the application of ESD and peptide.

[00107] This test demonstrated the usefulness and effectiveness of applying a self-assembly peptide to the post-ESD lesion site. There were no adverse effects related to the use of the self-assembly peptide. The self-assembly peptide helped to reduce the rate of post-ESD bleeding. The self-assembly peptide also promoted healing of the ulcer. The self-assembly peptides of the present description provided increased treatment and recovery of the tested individuals, indicating the effectiveness of using this peptide for the treatment of ESD-induced ulcers. Example 2: Verification of the effectiveness of the PuraMatrix ™ peptide hydrogel as a preventive stenosis after an endoscopic resection for large-scale early gastrointestinal cancer and precancerous lesions in humans.

[00108] The tests were performed on an individual having an ulcer (lesion) after an endoscopic resection of the esophageal cancer. As shown in Figure 2A, an early stage esophageal cancer with circumferential dispersion is shown, in which the cancer site covers a circular zone. Endoscopic dissection of the submucosa was performed, which created an ulcer. Figure 2B shows an artificial ulcer with 4/5 of the circumferential dispersion, in which the resection lesion covers 4/5 of a circular area, after the lesion undergoes resection using ESD. 4/5 of the circumferential dispersion can cause stenosis in the absence of application of a peptide solution to form a hydrogel.

[00109] After confirming that there was no bleeding on the surface of the artificial ulcer after an endoscopic resection, a catheter was passed through an endoscope, and a peptide solution, such as PuraMatrix ™ peptide hydrogel by 3-D Matrix, LTD. (2.5%, adequate dose (1 mL per 1 cm2)) in a syringe was uniformly coated on the ulcer surface. Figure 2C shows a coating of the peptide solution.

[00110] In the first week after surgery, an endoscope is used to assess the area. At this point, as with the initial round, the peptide solution is coated evenly on the ulcer surface. For the previous cases, an endoscope was used to perform a third and fourth evaluation of the area, in the fourth and eighth weeks, respectively, after the surgery that induced stenosis, to evaluate the effectiveness of the peptide solution coating. Figure 2D shows the treated area 4 weeks after surgery. The ulcer shows scarring, and the passage of the endoscope is possible in the direction of the stenosis. Figure 2E shows the treated area 8 weeks after surgery. The passage of the endoscope is possible in the direction of the stenosis.

[00111] The effectiveness of the peptide solution, such as a preventive stricture, has been demonstrated. In addition, no delayed bleeding or perforations were seen as side effects of endoscopic resection.

[00112] This example demonstrates the ability of the peptide solution to form a hydrogel on an ulcer surface to promote healing of the area and reduce stenosis.

Claims (18)

1. Kit for the prevention of stenosis subsequent to endoscopic mucosectomy (EMR) or endoscopic submucosal dissection (ESD) in one or more of the mouth, throat and esophagus in an individual, CARAC TE RIZADO for the fact that it comprises: a solution comprising sucrose and a self-assembly peptide comprising between 7 amino acids and 32 amino acids in an effective amount and in an effective concentration to form a hydrogel under physiological conditions to allow the prevention of stenosis; and instructions for administering the solution to a target area of the individual's mouth, throat or esophagus, where the self-assembling peptide is absent from a physiologically or biologically active motif or sequence that impairs the cell's intrinsic function, where the peptide in the solution comprises one of (RADA) P, where p = 2-50 (SEQ ID NO: 2), (IEIK) pI, where p = 2-50 (SEQ ID NO: 5), (RADA) 4 (SEQ ID NO: 10) and (IEIK) 3I (SEQ ID NO: 11). 2. Kit, according to claim 1, CARAC TE RI ZADO because it additionally comprises a catheter to introduce the solution into the individual's mouth, throat or esophagus. 3. Kit, according to claim 1, CHARACTERIZED by the fact that it additionally comprises instructions for diluting the solution to administer an effective concentration of the solution to the individual's mouth, throat or esophagus. 4. Kit according to claim 1, CHARACTERIZED by the fact that it additionally comprises instructions for determining the effective concentration of solution for the mouth, throat and esophagus in the individual based on a dimension of the mouth, throat and esophagus in the area target. 5. Kit, according to claim 1, CHARACTERIZED by the fact that the self-assembling peptide exhibits a beta-sheet structure in aqueous solution at the physiological pH level and / or a cation. 6. Kit, according to claim 1, CHARACTERIZED by the fact that the self-assembling peptide has a nanofiber diameter in a range from 10 nm to 20 nm, an average pore size is in a range from 5 nm to 200 nm, or a length of 5 nm. 7. Kit, according to claim 1, CHARACTERIZED by the fact that the solution consists essentially of an amphiphilic peptide comprising at least 12 amino acids that alternate between a hydrophobic amino acid and a hydrophilic amino acid. 8. Kit, according to claim 1, CHARACTERIZED by the fact that the solution additionally comprises at least one biologically active agent. 9. Use of a CARAC TE RI ZADO self-assembly peptide because it is in the preparation of a medication for the prevention of stenosis subsequent to endoscopic mucosectomy or endoscopic dissection of the submucosa in one or more of the mouth, throat and esophagus in an individual, in which the self-assembly peptide is supplied in a solution comprising a self-assembly peptide comprising between 7 amino acids to 32 amino acids in an effective amount and in an effective concentration to form a hydrogel under physiological conditions of the mouth, throat or esophagus to allow prevention stenosis, in which the self-assembly peptide is absent from a physiologically or biologically active motif or sequence that impairs the cell's intrinsic function, where the peptide in the solution comprises one of (RADA) p, where p = 2-50 (SEQ ID NO: 2) and (IEIK) PI, where p = 2-50 (SEQ ID NO: 5), RADA) 4 (SEQ ID NO: 10) and (IEIK) 3I (SEQ ID NO: 11). 10. Use, according to claim 9, CARAC TE RI ZADO by the fact that at least an effective amount and an effective concentration is based in part on a dimension of the target area of the endoscopic mucosectomy or endoscopic dissection of the submucosa in the mouth, throat or esophagus. 11. Use, according to claim 9, CARAC TE RI ZADO by the fact that the effective amount is 1 mL per 1 cm2 of target area. 12. Use, according to claim 9, CARAC TE RI ZADO because the effective concentration to allow the prevention of stenosis comprises a concentration in the range of 0.1 weight percent by volume to 3 weight percent per volume of peptide or the amount effective to prevent stenosis comprises a volume in the range of 0.1 ml to 5 ml. 13. Use, according to claim 9, CARAC TE RI ZADO because the solution is free of cells and / or drugs. 14. Use, according to claim 9, CARAC TE RI ZADO by the fact that the solution consists essentially of an amphiphilic peptide comprising at least 12 amino acids that alternate between a hydrophobic amino acid and a hydrophilic amino acid. 15. Use, according to claim 9, CARAC TE RI ZADO by the fact that the individual is a mammal. 16. Use, according to claim 9, CARAC TE RI ZADO because the solution is provided in a single dose. 17. Use, according to claim 9, CHARACTERIZED by the fact that the solution is provided in at least two doses. 18. Use, according to claim 9, CHARACTERIZED by the fact that the solution additionally comprises at least one biologically active agent.